Heart, Lung and Circulation

Losartan Improves Survival and Cardiac Function in a Double-mutant Mouse Model of Severe Hypertrophic Cardiomyopathy

      Background: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the myocardium, caused by sarcomere protein mutations. Five percent of HCM patients harbour multiple mutations leading to a more severe clinical phenotype (increased LV hypertrophy and incidence of sudden cardiac death events). Currently, there are no pharmacological therapies that have definitively been shown to prevent or cause regression of HCM. This study sought to investigate the role of the angiotensin II receptor inhibitor losartan in mice with severe HCM.
      Methods: The TnI-203/MHC-403 mouse model, which expresses two HCM-causing mutations and results in a severe phenotype resulting in heart failure and 100% mortality by 21 days, was used. This model mimics a subset of HCM patients who develop a dilated phenotype and heart failure. TnI-203/MHC-403 and non-transgenic (NTg) mice were treated with either losartan (100 mg/kg, oral, daily) or water alone (control group). Outcome measures included survival and cardiac function.
      Results: A total of n = 125 mice were treated with either losartan (n = 67) or water (n = 58). Losartan treatment significantly improved survival of TnI-203/MHC-403 mice, extending maximum lifespan by 35% (mean, 17.3 ± 1.6 days vs 23.3 ± 1.4 days; p < 0.0001). Echocardiographic analysis showed losartan treatment improved cardiac function in TnI-203/MHC-403 mice compared to water-treated TnI-203/MHC-403 mice (fractional shortening 54 ± 4% vs 40 ± 14%; p = 0.013). The improvement in survival in losartan-treated mice was independent of gender.
      Conclusion: Losartan treatment is beneficial in improving survival and cardiac function in a double-mutant mouse model of severe HCM. Further studies to investigate the molecular mechanisms underlying this response are warranted.